RU2508106C2 - Methods and compositions for treating schizophrenia with using atypical neuroleptic combined therapy - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and aims at treating schizophrenia. A method of treating, preventing, delaying the progression or onset and/or development of schizophrenia involves administering an effective amount of a combined therapy containing dimebon and risperidone into the patient. A pharmaceutically acceptable composition for treating, preventing, delaying the progression or onset and/or development of schizophrenia contains dimebon and risperidone. A kit for treating, preventing, delaying the progression or onset and/or development of schizophrenia contains dimebon and risperidone, and a package leaflet.

EFFECT: using the declared group of inventions enables increasing the clinical effect of treating schizophrenia.

7 cl

Description

BACKGROUND OF THE INVENTION

A Brief Overview of Schizophrenia

Schizophrenia dramatically worsens the health and well-being of people who suffer from this mental disorder, which is one of the most difficult and difficult to treat. Persons with schizophrenia (“schizophrenics”) may suffer from a myriad of symptoms and may require careful care and continuous drug and / or regimen therapy, which leads to significant socio-economic costs, even in the absence of hospitalization or institutionalization. Schizophrenia affects approximately 2 million Americans. The disease usually develops between puberty and age 30 and is characterized by one or more positive symptoms (e.g., illusions and hallucinations) and / or negative symptoms (e.g., delayed emotions and lack of interest) and / or disorganized symptoms (e.g., confused consciousness and speech) , or disorganized behavior and perception). Many studies have shown that schizophrenics have reduced ability to solve problems that require short-term oral working memory, quickly associated cognitive “prediction” or “expectation,” or long-term attention / alertness control. Schizophrenics who have auditory hallucinations (which are described for most affected individuals) also have a strongly correlated decrease in their speech perception abilities. Schizophrenics also have social and functional deficits, such as deficits and confusion in identifying the mood or reactions of others, in determining what the socially correct course of action is for them, and in identifying the causes of present and past actions or events. Schizophrenia is a chronic disorder, and most patients require ongoing treatment to alleviate or reduce the incidence of psychotic episodes. The causes of schizophrenia are largely unknown. Although it is believed to have a genetic component, environmental factors appear to influence the onset and severity of the disease.

A Brief Overview of Mechanistic Considerations in the Pathogenesis of Schizophrenia

Until recently, the attention of researchers working in the field of biochemistry of psychoses was mainly concentrated on two systems of mediators: the dopamine system and the serotonin system. The dopamine hypothesis came from the general ability of traditional (typical) antipsychotics to cause neurological side effects similar to the symptoms of Parkinson's disease. This same property also gave the drugs the common name for antipsychotics. The neurobiochemistry of parkinsonism is associated with an imbalance between dopamine and cholinergic systems in nigrostriatum, in which the activity of dopamine structures decreases, while the activity of cholinergic structures increases. The ability of typical antipsychotics to control productive semiology in patients with schizophrenic disorders (illusions, hallucinations, confusion) correlates with the ability to cause parkinsonism and comes from the properties of suppressing the activity of the dopamine system. Thus, it was concluded that the positive semiology of psychosis is a consequence of the excessive activity of the dopaminergic system. Another argument in favor of this result was the result of a study of dopamine metabolites in the spinal fluid. Higher levels of homovanilic acid (a product of dopamine metabolism) were found in patients with psychosis compared with healthy people. Currently, this hypothesis has been further developed under the influence of new data, including the results of a post-mortem examination of the brain and positron emission tomography of living patients. The important role of the regulator of dopamine receptors has been shown by a thorough study of changes in the function of the dopaminergic system under the influence of antipsychotic drugs. Several types of dopamine receptors have been described, each of which has its own localization and function features.

Dopaminergic agents, primarily dopamine receptor subtype D2 blockers, in particular haloperidol and chlorpromazine and many others, are widely used to treat patients with schizophrenia in accordance with the dopamine theory of schizophrenia. They effectively reduce the phase of acute psychosis in patients with schizophrenia, but are often much less effective in treating other phases of the disease. For this reason, in recent years, an intensive study was conducted to study the mechanism of the pathogenesis of schizophrenia and the development of new drugs for its effective treatment.

The second hypothesis suggests that the fundamental cause is a violation of the relationship between dopamine and serotonin systems. Serotonergic structures have a complex corrective effect on the function of the dopaminergic system, increasing its activity in the mesolimbic and mesostriatal structures and decreasing it in the prefrontal region, which determines the clinical phenomena of hypofrontal function. A weighty argument in favor of this hypothesis, as is usually believed, is the introduction of a prototype of atypical antipsychotics, clozapine, in clinical practice. The neurochemical spectrum of activity of clozapine distinguishes it from all antipsychotic drugs known at that time, since clozapine blocks serotonergic receptors mainly stronger than dopaminergic receptors. In addition, it turned out that it is effective against diseases in which primary disorders associated with deficits predominate, and also in most cases, which show resistance to traditional antipsychotic drugs. In addition, clozapine is much less likely to cause neuroleptic side effects of J.M. Kane, "The new antipsychotics," J. Pract. Psychiatry Behav. Health, 1997, 3: 343-354.

Data from a clinical study of second-generation antipsychotics (serotonin-dopamine blockers, the so-called atypical antipsychotics "AN"), showed the superiority of these drugs over first-generation antipsychotics (dopamine blockers "DB") in relation to their effect on the negative symptoms of schizophrenia , on persistent productive symptoms and neurocognitive impairment. Today, there are many hypotheses within which attempts are made to explain the pharmacodynamic mechanisms that lead to the superiority of AN over first-generation antipsychotics (the hypothesis of a predominant effect on the serotonin structures of suture nuclei, the hypothesis of a quick non-adhesive blockade of dopamine receptors, the hypothesis of the glutamate effects of clozapine). Bioclinic studies in the field of schizophrenia, including the successes of psychopharmacology, are finding more and more convincing facts indicating a relationship between the development and preservation of clinical symptoms and neurocognitive impairment in cases of schizophrenia and many neurochemical, neuroimmunological, biochemical, genetic and morphological characteristics.

The hypotheses described above have sufficient explanatory value with respect to the large body of facts. However, not all data fits into them. Blockade of dopaminergic receptors is known to occur much faster than the clinical effect develops. In addition, the degree of blockade of these receptors is the same in patients who respond well to antipsychotic therapy as in patients who are resistant to it (S. Heckers, "Neural models of schizophrenia," Dialogues in Clinical Neuroscience, 2000,2 (3): 267-280). On the other hand, attempts by psychopharmacologists to develop a drug with antipsychotic effects that would not affect the dopaminergic system have not been successful (S. Kapur, G. Remington, "Dopamine D (2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient, "Biol. Psychiatry, 2001, 50 (11): 873-83).

At the same time, not all practitioners look equally at the generational change of antipsychotic drugs. In addition, some are skeptical of the idea that second-generation drugs have a wider spectrum of effectiveness. Indeed, studies in which a therapeutic response to a first-generation drug is compared to a response to a second-generation drug does not show a significant advantage in controlling the productive symptoms of psychosis. This effect in particular is a traditional indicator of the therapeutic activity of an antipsychotic. Expanding the concept of the pharmacodynamics of antipsychotics and the potential reserve hidden in remission, which is achieved thanks to typical therapy, can be very important for reconsidering the attitude of practicing psychiatrists to new drugs.

In addition to the widely recognized importance of the dopamine and serotonin activity of antipsychotics for the implementation of their clinical activity, another neurotransmitter system attracts attention. This is the glutamatergic neurotransmitter system of the central nervous system (CNS). Since many researchers in recent years have been inclined to believe that cognitive impairment plays a fundamental role in the formation of schizophrenic impairment (NC Andreasen, "Schizophrenia: the fundamental questions," Brain Res. Rev., 2000, 31 (2-3): 106-12 ), the glutamatergic system attracts increasing interest, not only theoretically, but also practically (K. Hashimoto, M. Iyo, "Glutamate hypothesis of schizophrenia and targets for new antipsychotic drugs," Nihon Shinkei Seishin Yakurigaku Zasshi, 2002, 22 (1 ): 3-13). Stimulation of glutamatergic transmission can lead to stimulation of central nervous system activity, but at some point it can also lead to toxic effects on the brain. On the other hand, suppression of the glutamatergic system can lead to neuroprotective effects, but along with them, a cognitive deficit (S. Heckers, C. Konradi, "Hippocampal neurons in schizophrenia," J. Neural Transm., 2002.109 (5- 6): 891-905). Some researchers believe the ability to exert a glutamatergic effect as the only possible neurochemical mechanism for the anti-deficiency activity of clozapine (L. Chen, CR. Yang, "Interaction of dopamine Dl and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex," J. Neurophysiol, 2002, 87 (5): 2324-36). In addition, the glutamatergic system is credited with a role in coordinating the functioning of other conductive brain structures. This function can be carried out, in particular, due to the hypothetical ability of the cerebellum (in the functioning of which the glutamatergic system plays an important role) to form a temporary organization of mental processes (NC Andreasen, "Schizophrenia: the fundamental questions," Brain Res. Rev. 2000, 31 (2 -3): 106-12). Control of this function is hardly achievable for traditional antipsychotic drugs. However, the glutamate activity of clozapine in this regard entails the possibility of the formation of new hypotheses that explain its unusual clinical activity during a long course of treatment (L. Chen, CR. Yang, "Interaction of dopamine Dl and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex, "J. Neurophysiol, 2002; 87 (5): 2324-36) and the formation of new homeostatic bonds requiring a long period of time. Despite the instant blockade of dopamine receptors, the first symptoms of the clinical effect of antipsychotics (control of productive symptoms) appear gradually over more than a few weeks, and the patient's recovery lasts for many months.

Thus, along with the theory of the pathogenesis of schizophrenia, which was developed relatively long ago and widely accepted, where the main role is given to the hyperfunctioning of the dopaminergic neurotransmitter system of the central nervous system and also the imbalance in the serotonergic mediator system, there has recently been an intensive development of the theory of pathogenesis, where the main role in the development of this disease violations play in the glutamatergic neurotransmitter system of the central nervous system. It has been suggested that many of the elements of mental disturbance that are observed in patients with schizophrenia are associated with hypofunctioning of the glutamatergic system. Support for the glutamate theory of schizophrenia includes the fact that phencyclidine, an ion channel blocker of the NMDA receptor, one of the main subtypes of glutamate receptors, induces a complex of behavioral symptoms in healthy volunteers that are very similar to the behavior of patients with schizophrenia: they exhibit psychosis, autism, poor mood ; they become unable to solve problems (tests); they become eccentric and their speech and thinking deteriorate. Currently, the phencyclidine model of schizophrenia is believed to be the closest and most appropriate behavior for schizophrenia patients (R. M. Allen, S. J. Young, "Phencyclidine-induced psychosis," Amer. J. Psychiatry, 1976, 33: 1425-8). Similar effects are also caused by other NMDA receptor ion channel blockers, such as ketamine, and AMPA blockers, such as MK-801. Patients with schizophrenia have been shown to exhibit lower levels of glutamic acid in cerebrospinal fluid than normal people. It is also shown in subsequent studies that in the brain of patients with schizophrenia, there is an increase in the large diameter of glutamatergic fibers, which is 30% larger than in the brains of patients without schizophrenia, and that there is a simultaneous decrease in the small diameter of glutamatergic fibers by 78%. In addition, an increase in the number of NMDA receptors is observed in the cerebral cortex of patients with schizophrenia, but there is also a decrease in glutamate reuptake in the basal ganglia.

Brief Description of Hydrogenated Derivatives of Pyrido [4,3-b] Indole

Known compounds of the class of tetra- and hexahydro-1H-pyrido [4,3-b] indole derivatives exhibit a wide spectrum of biological activity. The following types of activity were found in the series of 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles: antihistamine activity (DE 1 813 229, filed December 6, 1968; DE 1 952 800, filed October 20 1969), central depressive and anti-inflammatory activity (US 3,718,657, filed December 3, 1970), antipsychotic activity (Herbert C A., Plattner SS, Welch WM, Mol. Pharm. 1980, v.17, No. 1, p. 38 -42) and others. Derivatives of 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole show psychotropic (Welch WM, Harbert CA., Weissman A., Koe BK, J. Med. Chem., 1986, vol.29, No. 10, p. 2093-2099), antiaggressive, antiarrhythmic and other types of activity.

It is known that certain drugs, such as diazolin (mebhydroline), dimebon, dorastine, carbidine (dicarbin), stobadine and gevotrolin, were derived from tetra- or hexahydro-1H-pyrido [4,3-b] indole derivatives. Diazolin (2-methyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride) (Klyuev MA, Drugs, used in "Medical Pract.", USSR, Moscow , "Meditzina" Publishers, 1991, p. 512) and dimebon (2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride) (MD Mashkovsky, "Medicinal Drugs" in 2 vol. Vol. 1,12th Edition, Moscow, "Meditzina" Publishers, 1993, p. 383), as well as dorastine (2-methyl -8-chloro-5- [2- (6-methyl-3-pyridyl) ethyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride) (USAN and USP dictionary of drugs names (United States Adopted Names, 1961-1988, current US Pharmacopoeia and National Formula for Drugs and other nonproprietary drug names), 1989, 26th Edition., p. 196), known as antihistamines; car idin (dicarbin) (cis (±) -2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole dihydrochloride) is an antipsychotic agent having antidepressant effect (LN Yakhontov, RG Glushkov, Synthetic Drugs, ed. by AG Natradze, Moscow, "Meditzina" Publishers, 1983, p.234-237), and its (-) isomer, stobadine, is known as an antiarrhythmic drug (Kitlova M., Gibela P., Drimal J., Bratisl. Lek Listy, 1985, vol. 84, No.5, p. 542-549); hevotroline, 8-fluoro-2- (3- (3-pyridyl) propyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride, is an antipsychotic and tranquilizer (Abou- Gharbi M., Patel UR, Webb MB, Moyer JA, Ardnee T.N., J. Med. Chem., 1987, vol. 30, p. 1818-1823). Dimebon has been used in medicine as an antiallergic drug (Copyright Certificate No. 1138164, IP Class A61K 31 / 47.5, C07 D 209/52, published February 7, 1985) in Russia for more than 20 years.

As described in US Pat. Nos. 6,187,785 and 7,021,206, hydrogenated pyrido [4,3-b] indole derivatives, such as dimebon, have NMDA antagonist properties that make them useful for treating neurodegenerative diseases such as Alzheimer's disease. As described in WO 2005/055951, hydrogenated pyrido [4,3-b] indole derivatives, such as dimebon, are useful in medicine or veterinary medicine as geroprotectors, for example, delaying the onset and / or development of an age-related or age-related manifestation and / or pathologies or conditions, including a disorder in the skin-hair outer skin, a visual disturbance, and a decrease in body weight. U.S. Patent Applications 11/543529 (US Publication No. 20070117835) and 11/543341 (US Publication No. 20070117834) disclose hydrogenated pyrido [4,3-b] indole derivatives, such as dimebon, as neuroprotective agents for use in the treatment of and / or preventing and / or slowing the progression or onset and / or development of Huntington's disease. Dimebon and / or its properties are also discussed in: Yu. Ya Ivanov et al., 2001; N.N. Lermontova et al., 2001; S.O. Bachurin et al, 2003and V.V. Grigor'ev et al., 2003.

Significant Medical Need

Significant interest and the need for additional or alternative therapies for the treatment, prevention and / or delay in the onset and / or development of schizophrenia remain. Preferably, new therapies should improve the quality of life for patients with schizophrenia and / or be accompanied by fewer side effects or less severe side effects compared to currently available therapies.

SUMMARY OF THE INVENTION

Methods, combination therapies, pharmaceutical compositions and kits for treating and / or preventing and / or delaying the onset and / or development of schizophrenia using hydrogenated [4,3-b] indole and an atypical antipsychotic or a pharmaceutically acceptable salt of any of these are described. The invention encompasses combination therapies having a first and second compound, wherein the first compound is a hydrogenated [4,3-b] indole, described in detail herein, and the second compound is an atypical antipsychotic. The invention particularly encompasses combination therapy in which the first compound is dimebon (2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride) and the second compound is an atypical antipsychotic, especially risperidone (3- [2- [4- (6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl ] ethyl] -2-methyl-6,7,8,9-tetrahydropyrido [2,1-b] pyrimidin-4-one) or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention encompasses a method of: (a) treating schizophrenia in humans; (b) slowing the progression of schizophrenia in a person who has been diagnosed with schizophrenia; or (c) preventing or delaying the development of schizophrenia in a person who is at risk of developing schizophrenia, including administering to the person an effective amount of combination therapy. In one embodiment, the method is a method of alleviating one or more positive symptoms of schizophrenia by administering to an individual an effective amount of combination therapy. In one embodiment, the method is a method of alleviating one or more negative symptoms of schizophrenia by administering to an individual an effective amount of combination therapy. In one embodiment, the method is a method of alleviating one or more disorganized symptoms of schizophrenia by administering to an individual an effective amount of combination therapy. In one embodiment, the method is a method of alleviating one or more symptoms of schizophrenia by administering to a person an effective amount of combination therapy. In one embodiment, the method is a method of alleviating the positive and negative symptom of schizophrenia by administering to the person an effective amount of combination therapy. In another embodiment, the method is a method of alleviating a positive and disorganized symptom of schizophrenia. In yet another embodiment, the method is a method of alleviating the negative and disorganized symptom of schizophrenia by administering to the person an effective amount of combination therapy. In one embodiment, combination therapy antipsychotic is administered at a dose that is less than that required for individual / monotherapy with the same atypical antipsychotic, giving a comparable therapeutic effect. Also included within the scope of the invention are methods of enhancing a human response to an atypical antipsychotic, including administering a first compound, such as dimebon, in combination with an atypical antipsychotic. The invention also includes methods of treating schizophrenia by administering combination therapy comprising dimebon and an atypical antipsychotic, the combination therapy being administered in an amount effective to improve the cognitive symptom of schizophrenia. Particularly, the invention encompasses combination therapies that cause an improvement in cognitive function in humans. The invention encompasses methods that enhance a person’s cognitive ability (improve cognition / memory of numbers and / or the severity of cognitive symptoms associated with schizophrenia) to a greater extent than the use of atypical antipsychotics as individual / monotherapy (and in the absence of the first compound, such as dimebon) in the same or similar patients. The invention also encompasses pharmaceutical compositions for combination therapy, including unit forms thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the framework of the present description, unless otherwise indicated, the use of the singular implies "one or more".

A reference to “approximately” with respect to a quantity or parameter includes (and describes) embodiments that are directed to that quantity or parameter per se. For example, a description relating to “approximately X” includes a description of “X”.

For the purposes of the invention, “combination therapy” refers to therapy comprising the first compound and the second compound, the first compound being hydrogenated pyrido [4,3-b] indole as described herein, and the second compound being an antipsychotic, and where the first the compound is used in combination with the second compound. A therapy comprising dimebon used in combination with risperidone is an example of the combination therapy of the invention. Administration of the first compound “in combination with” the second compound includes the administration of compounds in the same or another composition, sequentially, simultaneously or continuously. Administration in combination encompasses any circumstance in which the first compound and the second agent are administered to a person in an effective amount. As discussed below, it is understood that the first compound and the second compound can be administered at different frequencies and / or intervals of administration and can be administered using the same route of administration or different routes of administration. For example, administration “in conjunction with” includes an administration regimen according to which the first compound (such as dimebon) of the combination therapy is administered three times a day, and the second compound (such as risperidone) of the combination therapy is administered once a day, and wherein the first the daily dose of the first compound is administered simultaneously with the second compound, and where the second and third daily doses of the first compound are administered individually. It is further understood that various modes of administration may vary during the course of administration. For example, in combination therapy, including dimebon and risperidone, dimebon may be administered once a day, and risperidone may be administered once a week or less than once a day. In some embodiments, combination therapy, if necessary, includes one or more pharmaceutically acceptable carriers or excipients, pharmaceutically inactive compounds and / or inert substances. Thus, the compounds in the combination therapy of the invention can be administered sequentially, simultaneously or continuously using the same or different routes of administration for each compound.

It is also understood and clearly follows from the present description that the reference to the “first compound” includes and refers to any hydrogenated pyrido [4,3-b] indole or its pharmaceutically acceptable salt or other form, as described herein, such as a dimebon compound.

It is also understood and clearly follows from the present description that reference to the “second compound” of combination therapy includes and relates to an atypical antipsychotic or a pharmaceutically acceptable salt thereof.

As used herein, the term "schizophrenia" includes all forms and classifications of schizophrenia known in the art, including, but not limited to, the catatonic type, hebephrenic type, disorganized type, paranoid type, residual type or undifferentiated type of schizophrenia and deficient syndrome and / or described in the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Washington DC, 2000 or in the International Statistical Classification of Diseases and Related Health Problems, or otherwise known to specialists.

As used herein, the term “atypical antipsychotic” refers to an antipsychotic that reduces or eliminates the activity of the 5-HT2A receptor and the D2 receptor. In some embodiments, an atypical antipsychotic reduces the activity of the serotonin-2A receptor (5-HT2A) and the dopamine-2 receptor (D2) by at least or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared with the corresponding activity in the same patient before treatment with an atypical antipsychotic or compared with the corresponding activity in other patients not receiving an atypical antipsychotic. In some embodiments, the atypical antipsychotic is capable of binding to the active center of at least one of the 5-HT2A receptor and the D2 receptor (eg, ligand binding site). In some embodiments, the atypical antipsychotic is capable of binding to the allosteric site of at least one of the 5-HT2A receptor and the D2 receptor. The interaction between the atypical antipsychotic and the 5-HT2A receptor and the D2 receptor may be reversible or irreversible. In some embodiments, an atypical antipsychotic reduces the number or extent of motor side effects, such as EPS and tardive dyskinesias, compared with typical antipsychotics administered to the same or other patients in standard doses. Examples of atypical antipsychotics include risperidone (3- [2- [4- (6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl] -2-methyl-6,7,8,9- tetrahydropyrido [2,1-b] pyrimidin-4-one); clozapine (3-chloro-6- (4-methylpiperazin-1-yl) -5H-benzo [c] [1,5] benzodiazepine); olanzapine (2-methyl-4- (4-methylpiperazin-1-yl) -5H-thieno [3,2-c] [1,5] benzodiazepine); quetiapine (2- [2- (4-benzo [b] [1,5] benzothiazepin-6-ylpiperazin-1-yl) ethoxy] ethanol) and ciprasidone (5- [2- [4- (1,2-benzothiazole -3-yl) piperazin-1-yl] ethyl] -6-chloro-1,3-dihydroindol-2-one); olanzapine / fluoxetine (available as Symbyax); aripiprazole (7- [4- [4- (2,3-dichlorophenyl) piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinolin-2-one; paliperidone (3- [2- [4- (6-fluorobenzo [d] isoxazol-3-yl) -1-piperidyl] ethyl] -7-hydroxy-4-methyl-1,5-diazabicyclo [4.4.0] deca-3,5-dien-2-one ); sertindole (1- [2- [4- [5-chloro-1- (4-fluorophenyl) -indol-3-yl] -1-piperidyl] ethyl] imidazolidin-2-one); zotepine (2- ( (8-chlorodibenzo (b, f) thiepin-10-yl) oxy) -N, N-dimethylethylamine); amisulpride (4-amino-N - [(1-ethylpyrrolidin-2-yl) methyl] -5-ethylsulfonyl- 2-methoxy-benzamide); bifeprunox (7- [4 - [(3-phenylphenyl) methyl] piperazin-1-yl] -3H-benzoxazol-2-one); and melperone (1- (4-fluorophenyl) -4 - (4-methyl-1-piperidyl) buta n-1-one).

In the framework of the invention, “treatment” is an approach to obtain a beneficial or desired result, including clinical results (eg, reducing the severity or duration, stabilizing the severity, or eliminating one or more symptoms (biochemical, histological and / or behavioral) of schizophrenia). For the purposes of this invention, useful or desirable results include, but are not limited to, alleviating the symptoms associated with schizophrenia, reducing the onset of symptoms associated with schizophrenia, preventing worsening of symptoms associated with schizophrenia, including positive and / or negative and / or disorganized symptoms . Treatment includes improving the quality of life of people with schizophrenia, reducing the dose of other medications needed to treat schizophrenia, delaying the progression of schizophrenia, and / or prolonging the survival of patients with schizophrenia. Preferably, treatment with the combination therapy disclosed herein does not cause or cause fewer side effects than is usually associated with the administration of antipsychotic drugs such as extrapyramidal side effects (EPS), acute dystonia, acute dyskinesia and tardive dyskinesia. In one embodiment, treatment with the combination therapy of the invention reduces or eliminates the number or degree of cognitive symptoms of schizophrenia (relieves cognitive dysfunction), compared with the same or similar patients who are receiving monotherapy with an atypical antipsychotic.

In the description, unless otherwise indicated, “patient” as used herein, means a mammal, including, but not limited to, a human. The patient may be a person who has been diagnosed or suspected, or there is a risk of her development, schizophrenia. The patient may be a person who exhibits one or more symptoms associated with schizophrenia. The patient may be a person who, due to heredity or for other reasons, is predisposed to the development of schizophrenia.

In the framework of the invention, unless otherwise indicated, combination therapy can be administered to the patient in any available dosage form. The first and second combination therapy may be administered in the same or different dosage forms, and the invention includes these various dosage forms. In one embodiment, at least one compound, or both the first and second compounds, of the combination therapy is administered to the patient as a conventional immediate release dosage form. In one embodiment, at least one compound, or both the first and the second compound, of combination therapy is administered to the patient in the form of a sustained release or as part of a sustained release system, such as a system capable of maintaining the rate of release of a compound into a patient for a desired period that may have an extended duration, such as a duration exceeding the time required to be released by the corresponding dosage form, directly released I have the same amount (eg, in a weight or molar basis) of the compound, and may be hours or days. The desired duration may be at least the half-life of the compound to be administered and may be, for example, at least about 6 hours or at least about 12 hours, or at least about 24 hours, or at least about 30 hours, or at least about 48 hours, or at least about 72 hours, or at least about 96 hours, or at least about 120 hours, or at least about 144 or more hours, and may be equal to at least about one week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 8 weeks, or at least about 16 weeks or more.

The term "effective amount" means such an amount of a compound (for example, a component of the combination therapy of the invention) or combination therapy, which in combination with its effectiveness and toxicity parameters, as well as based on the knowledge of the practitioner, should be effective in this therapeutic form . As understood in the prior art, an effective amount may be in one or more doses, that is, to achieve the desired treatment result, a single dose or multiple doses may be needed. In some embodiments, an effective amount of the compound or combination therapy is an amount sufficient to reduce the activity of the 5HT2A receptor and the D2 receptor, for example, to reduce these activities by at least or about 10%, 20%, 30%, 40% , 50%, 60%, 70%, 80%, 90%, 95% or 100% compared with the corresponding activity in the same patient before treatment or compared with the corresponding activity in other patients not receiving combination therapy. Standard methods can be used to measure the magnitude of this effect, such as in vitro analysis with purified enzyme, cell test, animal models, or human studies. An effective amount of combination therapy includes the amount of the first compound and the amount of the second compound of therapy, which, when administered sequentially, simultaneously or continuously, produce the desired result.

In various embodiments, treatment with combination therapy can lead to an additive or even synergistic (for example, greater than additive) result compared to the individual administration of the first or second compound. In some embodiments, a lower amount of each of the first and second compounds is used as part of the combination therapy compared to the amount of each component commonly used for individual (non-combination) therapy. Preferably, when using combination therapy, the same or greater therapeutic effect is obtained than when using any individual compound individually. In some embodiments, the same or greater therapeutic effect is obtained using a smaller amount (for example, a lower dose or less frequent administration) of the pharmaceutically active compound in combination therapy than the amount commonly used for individual therapy. Preferably, using a smaller amount of a second compound, such as the atypical antipsychotic risperidone, will reduce the number, severity, frequency or duration of one or more side effects associated with this compound. Suitable doses of any of the compounds that are administered in combination with each other as part of combination therapy can, if necessary, be reduced due to the combined action (for example, additive or synergistic effects) of the compounds.

The term "simultaneous administration" in the framework of the invention means that the first compound and the second compound in combination therapy are administered with a time division of not more than about 15 minutes, for example, not more than about 10, 5 or 1 minute. When the compounds are administered simultaneously, the first and second compounds may be contained in the same composition (for example, a composition comprising both hydrogenated pyrido [4,3-b] indole, such as dimebon, and an atypical antipsychotic, such as risperidone) or individual compositions (for example, hydrogenated pyrido [4,3-b] indole, such as dimebon, is contained in one composition, and an atypical antipsychotic, such as risperidone, is contained in another composition).

For the purposes of the invention, the term “sequential administration” means that the first compound and the second compound in combination therapy are administered with a time separation of more than about 15 minutes, for example, more than about 20, 30, 40, 50, 60 or more minutes. First, either the first compound or the second compound may be introduced. The first and second compounds for sequential administration are contained in separate compositions, which may be contained in the same or different packages or kits.

The combination therapy compound / component can be formulated with suitable vehicles for any available delivery route, whether in the form of an immediate release or in the form of a sustained release, including oral, through the mucous membrane (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery route. The compound may be formulated with suitable carriers to provide delivery forms, which may be, but not necessarily, sustained release forms, which include, but are not limited to: tablets, droplets, capsules (such as hard gelatine capsules and soft elastic gelatin capsules), wafers, lozenges, lozenges, chewing gums, dispersions, suppositories, ointments, cataplasmas (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g. nasal sprays and inhalations), gels, suspensions (on for example, aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. The first compound and the second combination therapy agent may be formulated with suitable carriers for the same or different routes of administration, and may be formulated for simultaneous administration through the same route of administration.

The first and second combination therapy compound can be used separately or together in the preparation of a composition, such as a pharmaceutical composition, by combining the compound or compounds as active ingredients with a pharmacologically acceptable carrier that are known in the art. Depending on the therapeutic form of the system (for example, a transdermal patch or oral tablet), the carrier may be in various forms. In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, regulators, salts for regulating the osmotic pressure, buffers, coating agents or antioxidants. Preparations containing the active ingredient may also contain other substances that have valuable therapeutic properties. The therapeutic forms may be presented in a conventional unit dose and may be prepared in a known pharmaceutical manner. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 ^th ed. (2000), which is incorporated herein by reference.

The amount of the combination therapy compound / component in the delivery form may be any effective amount. In one embodiment, the combination therapy comprises a first compound, such as dimebon, in a dosage form in an amount of from about 10 ng to about 1500 mg or more. In one embodiment, combination therapy comprises a second compound, such as risperidone, in a dosage form in an amount of from about 10 ng to about 1500 mg or more. In one embodiment, combination therapy comprises dimebon as the first compound in a delivery form, such as a sustained release system, in an amount that is less than about 30 mg of dimebon. In one embodiment, the combination therapy includes dimebon as the first compound in a delivery form, such as a separate sustained release system suitable for administration of dimebon for several days, where this form includes such a quantity of dimebon that the daily dose of dimebon is less than about 30 mg.

A treatment regimen comprising a dosage form of a first and / or second compound of combination therapy, whether in the form of an immediate release or as a sustained release system, may include administering the first and / or second compound to a patient at a dose of from about 0.1 to about 10 mg / kg of body weight at least once a day and for the period of time necessary to achieve a therapeutic effect. In other embodiments, the daily dose (or other frequency of administration) of the first and / or second compound is from about 0.1 to about 8 mg / kg; or from about 0.1 to about 6 mg / kg; or from about 0.1 to about 4 mg / kg; or from about 0.1 to about 2 mg / kg; or from about 0.1 to about 1 mg / kg; or from about 0.5 to about 10 mg / kg; or from about 1 to about 10 mg / kg; or from about 2 to about 10 mg / kg; or from about 4 to about 10 mg / kg; or from about 6 to about 10 mg / kg; or from about 8 to about 10 mg / kg; or from about 0.1 to about 5 mg / kg; or from about 0.1 to about 4 mg / kg; or from about 0.5 to about 5 mg / kg; or from about 1 to about 5 mg / kg; or from about 1 to about 4 mg / kg; or from about 2 to about 4 mg / kg; or from about 1 to about 3 mg / kg; or from about 1.5 to about 3 mg / kg; or from about 2 to about 3 mg / kg; or from about 0.01 to about 10 mg / kg; or from about 0.01 to 4 mg / kg; or from about 0.01 mg / kg to 2 mg / kg; or from about 0.05 to 10 mg / kg; or from about 0.05 to 8 mg / kg; or from about 0.05 to 4 mg / kg; or from about 0.05 to 4 mg / kg; or from about 0.05 to about 3 mg / kg; or from about 10 kg to about 50 kg; or from about 10 to about 100 mg / kg or from about 10 to about 250 mg / kg; or from about 50 to about 100 mg / kg or from about 50 to 200 mg / kg; or from about 100 to about 200 mg / kg or from about 200 to about 500 mg / kg; or more than about 100 mg / kg; or more than about 500 mg / kg. In some embodiments, a daily dose of dimebon is administered as a first combination therapy compound such as a daily dose of dimebon of less than about 0.1 mg / kg, which may include, but is not limited to, a daily dose of about 0.05 mg / kg. In one embodiment, the daily dose (by weight) of the first compound (such as dimebon) is approximately 10 times the daily dose (by weight) of the second compound (such as risperidone). For example, in one embodiment, combination therapy comprises administering a daily dose of approximately 60 mg of dimebon and a dose of approximately 6 mg of risperidone.

Combination therapy may be administered to a patient in accordance with an effective administration regimen over a desired period or period of time, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one embodiment, combination therapy is administered on a daily or fuzzy basis throughout a patient's life.

The frequency of administration of the first and / or second compound in combination therapy may be once a week. The frequency of administration of the first and / or second compound in combination therapy may be once a day. The frequency of administration of the first and / or second compound in combination therapy may be greater than about once a week. The frequency of administration of the first and / or second compound in combination therapy may be less than three times a day. The frequency of administration of the first and / or second compound in combination therapy may be less than about three times a day. The frequency of administration of the first and / or second compound in combination therapy can be approximately three times a week. The frequency of administration of the first and / or second compound in combination therapy can be approximately four times a week. The frequency of administration of the first and / or second compound in combination therapy can be approximately twice a week. The frequency of administration of the first and / or second compound in combination therapy may be more than once a week, but less than about once a day. The frequency of administration of the first and / or second compound in combination therapy can be approximately once a month. The frequency of administration of the first and / or second compound in combination therapy can be approximately twice a week. The frequency of administration of the first and / or second compound in combination therapy may be more than about once a month, but less than about once a week. The frequency of administration of the first and / or second compound in combination therapy can be variable (for example, once a day for 7 days, then without administration for 7 days, with a repeat of the cycle every 14 days, for example, for about 2 months, approximately 4 months, approximately 6 months or more). The frequency of administration of the first and / or second compound in combination therapy may be constant (for example, once a week for many weeks). At any of the frequencies of administration, any of the compounds described herein may be used together with any of the doses described here, for example, the frequency of administration of the first compound in combination therapy may be daily at a dose of less than 0.1 mg / kg or less than about 0 , 05 mg / kg dimebon. In one embodiment, the administration of the first compound is carried out three times a day, and the administration of the second compound once a day. In a particular embodiment, combination therapy includes the administration of dimebon three times a day (for example, approximately 20 mg 3 times a day) and the administration of risperidone once a day (for example, approximately 6 mg once a day).

Ways to Treat Schizophrenia

Hydrogenated pyrido [4,3-b] indoles and the atypical antipsychotics described herein can be used in combination therapy to treat and / or prevent and / or delay the onset and / or development of schizophrenia. As shown in Example 1, a representative of hydrogenated pyrido [4,3-b] indoles, dimebon is able to reduce the blocking effect of MK-801 on NMDA-induced currents in cultured rat hippocampal neurons. Examples of methods for determining the ability of hydrogenated pyrido [4,3-b] indoles to treat and / or prevent and / or delay the onset and / or development of schizophrenia are described in Examples 2 and 3. An ongoing clinical trial, including combination therapy, is described in Example 4.

It was unexpectedly discovered that dimebon, although it is an NMDA receptor blocker, can also reduce the blocking activity of MK-801 at NMDA receptors. Since phencyclidine and MK-801 have been found to act according to the same mechanism, competing for the same segment within the NMDA receptor channel, it is expected that the first compounds described here, such as dimebon, will reduce the blocking effect of phencyclidine on the NMDA receptor in exactly the same way. Since the psychotomimetic properties of phencyclidine are due to its ability to stably bind to a specific segment in the ion channel of the NMDA receptor and block the ion currents passing through its ion channel, the weakening of this blocking effect by the compounds described here, such as compounds of Formulas (1), (2) , (A) or (B), should result in a decrease in the psychotomimetic properties of phencyclidine.

Atypical antipsychotics have been used in the treatment of schizophrenia. For example, risperidone is an atypical antipsychotic that has been approved in the United States for the treatment of schizophrenia. Risperidone is available in tablet form in doses ranging from 0.25 mg to 4 mg, an oral solution, for example, at a dose of 1 mg / ml, and in the form of splittable tablets, for example, in doses ranging from 0.5 to 4 mg. However, the use of atypical antipsychotics is not without side effects, such as the potential development of tardive dyskinesia and extrapyramidal symptoms (ESP). Some atypical antipsychotics may also have limited use in some groups of patients.

Combination therapies that include the first and second compounds, where the first compound is hydrogenated pyrido [4,3-b] indole, especially the dimebon compound, and the second compound is an atypical antipsychotic, may have increased activity with respect to treatment, prevention and / or delays in the onset and / or development of schizophrenia. In particular, the combination therapies of the invention include hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof in combination with an atypical antipsychotic useful for treating, preventing and / or delaying the onset and / or development of schizophrenia. Methods that use such combination therapies can lead to an additive or even synergistic (for example, greater than additive) result compared to the individual administration of any combination therapy combination.

In one embodiment, combination therapy comprising the first and second compound requires lower doses of the individual compounds than would be necessary if the individual compounds were administered individually. This reduced dosage can reduce the side effects associated with the therapies and, to the best extent, lead to agreement on the part of the patient, which is very desirable for a population of patients with schizophrenia. Thus, in some embodiments, a lower amount of each pharmaceutically active compound is used as part of combination therapy compared to the amount commonly used for individual therapy. In some embodiments, the same or greater therapeutic effect is achieved by using a smaller amount (for example, a lower dose or less frequent administration) of the pharmaceutically active compound in combination therapy than the amount commonly used for individual therapy. Preferably, the use of a small amount of a pharmaceutically active compound results in a reduction in the number, severity, frequency or duration of one or more side effects associated with the compound.

Thus, the present invention relates to various methods that use combination therapy, such as those described in the "Summary of the Invention" and elsewhere in the present description. For example, in one embodiment, the present invention relates to a method for treating schizophrenia in a patient, comprising administering to the patient an effective amount of a combination therapy comprising hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) and an atypical antipsychotic (such like risperidone). In one embodiment, the present invention relates to a method for delaying the onset and / or development of schizophrenia in a patient at risk of developing schizophrenia (for example, a patient whose one or more family members have had schizophrenia, or a patient who has been diagnosed with a genetic mutation associated with with schizophrenia, or a patient who exhibits behavior characteristic of the onset of schizophrenia), including the introduction to the patient an effective amount of combination therapy, including hydrogenated pyrid [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) and the atypical antipsychotic (such as risperidone). In one embodiment, the present invention relates to a method for delaying the onset and / or development of schizophrenia in a patient who is genetically predisposed to develop schizophrenia, comprising administering to the patient an effective amount of combination therapy comprising hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) and an atypical antipsychotic (such as risperidone). In one embodiment, the present invention relates to a method for delaying the onset and / or development of schizophrenia in a patient having a mutant or abnormal gene associated with schizophrenia (such as the NRG1 or DTNBP1 gene) but which has not been diagnosed with schizophrenia, comprising administering to the patient an effective amount combination therapy, including hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) and an atypical antipsychotic (such as risperidone). In one embodiment, the present invention relates to a method for the prevention of schizophrenia in a patient who is genetically predisposed to develop schizophrenia or who has a mutant or abnormal gene associated with schizophrenia but who has not been diagnosed with schizophrenia, comprising administering to the patient an effective amount of combination therapy including hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) and an atypical antipsychotic (such as risperidone). In one embodiment, the present invention relates to a method for preventing the onset and / or development of schizophrenia in a patient who is not identified as genetically predisposed to the development of schizophrenia, comprising administering to the patient an effective amount of a combination therapy comprising hydrogenated pyrido [4,3-b] indole or its a pharmaceutically acceptable salt (such as dimebon) and an atypical antipsychotic (such as risperidone). In one embodiment, the present invention relates to a method for reducing the intensity or severity of schizophrenia symptoms in a patient diagnosed with schizophrenia, comprising administering to the patient an effective amount of combination therapy comprising hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) and an atypical antipsychotic (such as risperidone). In one embodiment, the present invention relates to a method for improving the quality of life of a patient diagnosed with schizophrenia, comprising administering to the patient an effective amount of a combination therapy comprising hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) and atypical antipsychotic (such as risperidone). In one embodiment, the method comprises preparing a medicament for combination therapy for use in any of the methods described, for example, treating and / or preventing and / or delaying the onset or development of schizophrenia.

Thus, the invention relates to methods for treating schizophrenia, comprising administering hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) in combination with an atypical antipsychotic (such as risperidone) in which the patient has (or he is suspected of having schizophrenia. Methods for administering an atypical antipsychotic, such as risperidone, are known in the art. A reduction in the dose of an atypical antipsychotic such as risperidone (which reduces the dependence on the administration of these drugs and actually delays the administration of these drugs) can be estimated, for example, by comparison with known and / or established average doses (in terms of quantity and / or intervals) that are known in the art.

In another aspect, the invention provides methods for enhancing the treatment of schizophrenia with an atypical antipsychotic comprising administering an effective amount of a hydrogenated pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof (such as dimebon) in combination with an atypical antipsychotic (such as risperidone). Treatment enhancement can be established by evaluating known parameters and / or indicators (such as the number and / or severity of symptoms and / or clinical and / or psychometric and / or neurocognitive and / or biological markers or scores) in a patient who is receiving combination therapy, compared with the same parameters and / or indicators in the same or similar patients who receive monotherapy using an atypical antipsychotic or who do not receive combination therapy, including the first compound such as dimebon.

Hydrogenated Pyrido [4,3-b] Indoles for Use in Methods, Compositions, Sets and Inventions Disclosed Here

When reference is made to organic residues or groups having a certain number of carbon atoms, unless otherwise indicated, it applies to all geometric and other isomers. For example, “butyl” includes n-butyl, sec-butyl, isobutyl and tert.-butyl; "propyl" includes n-propyl and isopropyl.

The term “alkyl” includes linear, branched or cyclic hydrocarbon structures and combinations thereof. Preferred alkyl groups are those having 20 carbon atoms (C20) or less. More preferred alkyl groups are those which have less than 15 or less than 10 or less than 8 carbon atoms.

The term "lower alkyl" refers to alkyl groups containing from 1 to 5 carbon atoms. Examples of lower alkyls include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl and the like. Lower alkyl is a subpopulation of alkyl.

The term “aryl” or (“Ar”) refers to an unsaturated aromatic carbocyclic group containing from 6 to 14 carbon atoms, having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or antryl), which may or may not be be aromatic (e.g. 2-benzoxazolinone, 2H-1,4-benzoxain-3 (4H) -one-7-yl), and the like. Preferred aryls include phenyl and naphthyl.

The term “heteroaryl” refers to an aromatic carbocyclic group containing from 2 to 10 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring. Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple fused rings (e.g., indolisinyl or benzothienyl). Examples of heteroaryl residues include, for example, imidazolyl, pyridinyl, indolyl, thiophenyl, thiazolyl, furanyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl, tetrazolyl and pyrazolyl.

The term “aralkyl” refers to a residue in which an aryl group is attached to the parent structure through an alkyl residue. Examples are benzyl, phenethyl and the like.

The term “heteroaralkyl” refers to a residue in which a heteroaryl group is attached to the parent structure through an alkyl residue. Examples include furanylmethyl, pyridinylmethyl, pyrimidinylethyl and the like.

The term “substituted heteroaralkyl” refers to heteroaryl groups which are substituted with 1 to 3 substituents, such as residues selected from the group consisting of hydroxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aryl, carboxyl, halogen, nitro and amino .

The term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

Hydrogenated pyrido [4,3-b] indoles or their pharmaceutically acceptable salts, such as from a salt with an acid or base, are the first combination therapy combination containing hydrogenated pyrido [4,3-b] indole and an atypical antipsychotic. The hydrogenated pyrido [4,3-b] indole may be tetrahydro pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof. The hydrogenated pyrido [4,3-b] indole may also be hexahydro pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof. Hydrogenated pyrido [4,3-b] indoles may be substituted with 1 to 3 substituents, although unsubstituted hydrogenated pyrido [4,3-b] indoles or hydrogenated pyrido [4,3-b] indoles with more than 3 substituents may also be considered. Suitable substituents include, but are not limited to, alkyl, lower alkyl, aralkyl, heteroaralkyl, substituted heteroaralkyl, and halogen.

Particular examples of hydrogenated pyrido [4,3-b] indoles are illustrated by Formulas A and B:

или

or

where R ^{1 is} selected from the group consisting of alkyl, lower alkyl and aralkyl, R ^{2 is} selected from the group consisting of hydrogen, aralkyl and substituted heteroaralkyl; and R ^{3 is} selected from the group consisting of hydrogen, alkyl, lower alkyl and halogen.

In one embodiment, R^one denotes an alkyl, such as alkyl selected from the group consisting of C_one-C_fifteenalkyl, C₁₀-C_fifteenalkyl, C_one-C₁₀alkyl C₂-C_fifteenalkyl C₂-C₁₀alkyl C₂-C₈alkyl C_four-C₈alkyl C₆-C₈alkyl C₆-C_fifteenalkyl, C_fifteen-C_twentyalkyl; C_one-C₈alkyl and C_one-C₆alkyl. In one embodiment, R^one denotes aralkyl. In one embodiment, R^one denotes lower alkyl, such as lower alkyl selected from the group consisting of C_one-C₂alkyl, C_one-C_fouralkyl, C₂-C_fouralkyl, C_one-C₅alkyl, C_one-C₃alkyl and C₂-C₅alkyl.

In one embodiment, R ¹ denotes a straight chain alkyl group. In one embodiment, R ¹ denotes a branched alkyl group. In one embodiment, R ¹ denotes a cyclic alkyl group.

In one embodiment, R ¹ is methyl. In one embodiment, R ¹ is ethyl. In one embodiment, R ¹ is methyl or ethyl. In one embodiment, R ¹ is methyl or aralkyl, such as benzyl. In one embodiment, R ¹ is ethyl or aralkyl, such as benzyl.

In one embodiment, R ¹ is aralkyl. In one embodiment, R ¹ is aralkyl, wherein any of the alkyl or lower alkyl substituents listed in the previous paragraphs is further substituted with aryl (e.g., Ar-C ₁ -C ₆ alkyl, Ar-C ₁ -C ₃ alkyl, or Ar-C ₁ -C ₁₅ alkyl). In one embodiment, R ¹ is aralkyl, wherein any of the alkyl or lower alkyl substituents listed in the previous paragraphs is substituted with a single ring aryl residue. In one embodiment, R ¹ is aralkyl, wherein any of the alkyl or lower alkyl substituents listed in the previous paragraphs is further substituted with phenyl (e.g., Ph-C ₁ -C ₆ alkyl or Ph-C ₁ -C ₃ alkyl, Ph-C ₁ -C ₁₅ alkyl). In one embodiment, R ¹ is benzyl.

All options for R ¹ can be combined with any of the options stated below for R ² and R ³ , as if each combination of R ¹ , R ² and R ^{3 has} been specifically and individually listed.

In one embodiment, R ² is H. In one embodiment, R ² is aralkyl. In one embodiment, R ² denotes a substituted heteroaralkyl group. In one embodiment, R ² is hydrogen or aralkyl. In one embodiment, R ² denotes hydrogen or a substituted heteroaralkyl group. In one embodiment, R ² denotes an aralkyl group or a substituted heteroaralkyl group. In one embodiment, R ^{2 is} selected from the group consisting of hydrogen, an aralkyl group and a substituted heteroaralkyl group.

In one embodiment, R ² is aralkyl, where R ² can be any of the aralkyl groups noted above for R ¹ , as if each variant of the aralkyl listed for R ¹ was separately and individually listed for R ² .

In one embodiment, R ² is a substituted heteroaralkyl group, wherein the alkyl portion of heteroaralkyl may be any alkyl or lower alkyl, such as those mentioned above for R ¹ . In one embodiment, R ² is substituted heteroaralkyl, where heteroaryl is substituted with 1-3 C ₁ -C ₃ alkyl substituents (e.g., 6-methyl-3-pyridylethyl). In one embodiment, R ² is a substituted heteroaralkyl group, wherein heteroaryl is substituted with 1-3 methyl groups. In one embodiment, R ² is a substituted heteroaralkyl group, wherein heteroaryl is substituted with one lower alkyl substituent. In one embodiment, R ² is a substituted heteroaralkyl group, wherein heteroaryl is substituted with one C ₁ -C ₃ alkyl substituent. In one embodiment, R ² is a substituted heteroaralkyl group, wherein heteroaryl is substituted with one or two methyl groups. In one embodiment, R ² is a substituted heteroaralkyl group, wherein heteroaryl is substituted with one methyl group.

In other embodiments, R ² is any of the substituted heteroaralkyl groups described in the previous paragraph, wherein the heteroaryl portion of the heteroaralkyl group is a single ring heteroaryl group. In other embodiments, R ² is any of the substituted heteroaralkyl groups indicated in the previous paragraph, wherein the heteroaryl portion of the heteroaralkyl group is a multiple fused ring heteroaryl group. In other embodiments, R ² is any of the substituted heteroaralkyl groups indicated in the previous paragraph, wherein the heteroaralkyl moiety is pyridyl (Py).

In one embodiment, R² denotes 6-CH₃-3-py- (ch₂)₂-.

In one embodiment, R ³ is hydrogen. In other embodiments, R ³ is any of the alkyl groups noted above for R ¹ , as if each alkyl variant listed for R ¹ was individually and individually listed for R ³ . In another embodiment, R ³ is halogen. In one embodiment, R ³ is hydrogen or alkyl. In one embodiment, R ³ is halogen or alkyl. In one embodiment, R ³ is hydrogen or halogen. In one embodiment, R ^{3 is} selected from the group consisting of hydrogen, alkyl, and halogen. In one embodiment, R ³ is Br. In one embodiment, R ³ is I. In one embodiment, R ³ is F. In one embodiment, R ³ is Cl.

In a particular embodiment, the hydrogenated pyrido [4,3-b] indole is 2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -2,3,4,5-tetrahydro-1H- pyrido [4,3-b] indole or a pharmaceutically acceptable salt thereof.

Hydrogenated pyrido [4,3-b] indoles may be in the form of pharmaceutically acceptable salts, which are known in the art. Pharmaceutically acceptable salts include pharmaceutically acceptable salts with an acid. Examples of pharmaceutically acceptable salts include hydrochlorides or dihydrochlorides. In a particular embodiment, hydrogenated pyrido [4,3-b] indole is a pharmaceutically acceptable salt of 2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -2,3,4,5-tetrahydro -1H-pyrido [4,3-b] indole, such as 2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -2,3,4,5-tetrahydro-1H- pyrido [4,3-b] indole dihydrochloride (dimebon).

Private representatives of hydrogenated pyrido - ([4,3-b]) indoles can also be described by Formula (1) or Formula (2):

For compounds of the general Formula (1) or (2),

R^one denotes -CH₃, CH₃CH_2- or Phch₂-(benzyl);

R² denotes -H, Phch₂- or 6-CH₃-3-py- (ch₂)₂-;

R ³ is —H, —CH ₃ or —Br,

with any combination of the above substituents. All possible combinations of the substituents of Formulas (1) and (2) are considered as specific and individual compounds, as if each individual and individual compound was listed under the chemical name. Also contemplated are compounds of Formula (1) or (2), from which one or more possible groups from the above substituent groups are removed: for example, where R^one denotes -CH₃; R² denotes -H, Phch₂- or 6-CH₃-3-py- (ch₂)₂-; and R³ denotes -H, -CH₃ or -Br, or where R^one denotes -CH₃; R² denotes 6-CH₃-3-py- (ch₂)₂-; and R³ denotes -H, -CH₃ or -Br.

The above and any compound may be in the form of salts with pharmaceutically acceptable acids and in the form of quaternized derivatives.

The compound may be a compound of Formula (1), where R^one denotes -CH₃, R² denotes -H and R³ denotes -CH₃. In one embodiment, the compound has Formula (1), provided that the substituents are different from the case where R^one denotes -CH₃, R² denotes -H and R³ denotes -CH₃. The compound may be a compound of Formula (2), where R^one denotes -CH₃, CH₃CH₂- or PhCH₂-; R² denotes -H, PhCH₂- or 6-CH₃-3-py- (ch₂)₂-; R³ denotes -H, -CH₃ or -Br. The compound may be a compound of Formula (2), where R^one stands for CH₃CH₂- or PhCH₂-, R² denotes -H and R³ denotes -H; or compound where R^one denotes -CH₃, R² denotes Phch₂-, R³ denotes -CH₃; or compound where R^one denotes -CH₃, R² denotes 6-CH₃-3-py- (ch₂)₂-, and R³ denotes -CH₃; or compound where R^one denotes -CH₃, R² denotes -H, R³ denotes -H or -CH₃; or compound where R^one denotes -CH₃, R² denotes -H, R³ denotes -Br.

Compounds known from the literature that can be used in the methods disclosed herein include the following compounds:

1. cis (±) 2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole and its dihydrochloride;

2. 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole;

3. 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole;

4. 2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and its dihydrochloride;

5. 2-methyl-5- (2-methyl-3-pyridyl) ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and its sesquisulfate;

6. 2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and its dihydrochloride ( dimebon);

7. 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole;

8. 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and its methyl iodide;

9. 2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole and its hydrochloride.

In one embodiment, the compound is a compound of Formula A or B, and R^one selected from lower alkyl or benzyl; R² selected from hydrogen, benzyl or 6-CH₃-3-py- (ch₂)₂-, and R³ selected from hydrogen, lower alkyl or halogen, or any pharmaceutically acceptable salt thereof. In another embodiment, R^one selected from -CH₃, CH₃CH₂- or benzyl; R² selected from -H, benzyl, or 6-CH₃-3-py- (ch₂)₂-; and R³ selected from -H, -CH₃ or —Br, or any pharmaceutically acceptable salt thereof. In another embodiment, the compound is selected from the group consisting of: cis (±) 2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole in the form of a racemic mixture either in a substantially pure (+) or substantially pure (-) form; 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 2-methyl-5- (2-methyl-3-pyridyl) ethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 2-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole; or 2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole or any pharmaceutically acceptable salt of any of these compounds. In one embodiment, the compound is a compound of Formula A or B in which R^one denotes -CH₃, R² denotes -H and R³ denotes -CH₃, or any pharmaceutically acceptable salt thereof. The compound may have Formula A or B, where R^one denotes CH₃CH₂- or benzyl, R² denotes -H, and R³ denotes -CH₃ or be any pharmaceutically acceptable salt thereof. The compound may have Formula A or B, where R^one denotes -CH₃, R² denotes benzyl and R³ denotes -CH₃ or be any pharmaceutically acceptable salt thereof. The compound may have Formula A or B, where R^one denotes -CH₃, R² denotes 6-CH₃-3-py- (ch₂)₂- and R³ is —H, or is any pharmaceutically acceptable salt thereof. The compound may have Formula A or B, where R² denotes 6-CH₃-3-py- (ch₂)₂-, or be any pharmaceutically acceptable salt thereof. The compound may have Formula A or B, where R^one denotes -CH₃, R² denotes -H and R³ denotes -H or -CH₃, or be any pharmaceutically acceptable salt thereof. The compound may have Formula A or B, where R^one denotes -CH₃, R² denotes -H and R³ denotes -Br, or be any pharmaceutically acceptable salt thereof. The compound may have Formula A or B, where R^one selected from lower alkyl or aralkyl, R² selected from hydrogen, aralkyl or substituted heteroaralkyl and R³ selected from hydrogen, lower alkyl or halogen.

The compound for use in compositions, kits and methods may be 2,8-dimethyl-5- (2- (6-methyl-3-pyridyl) ethyl-2,3,4,5-tetrahydro-1H-pyrido [4, 3-b] indole or any pharmaceutically acceptable salt thereof, such as an acid salt, hydrochloride or dihydrochloride.

Any of the compounds disclosed herein having two stereo centers in the ring structure of pyrido [4,3-b] indole (for example, carbon 4a and 9b of compound (1)) includes compounds whose stereo centers are in cis or trans form. The composition may include such a compound in a substantially pure form, such as a composition of a substantially pure S, S or R, R or S, R or R, S compound. A composition of substantially pure compound means that the composition contains not more than 15% or not more than 10%, or not more than 5%, or not more than 3%, or not more than 1% of the impurity of the compound in another stereochemical form. For example, a composition of substantially pure S, S compound means that the composition contains not more than 15% or not more than 10%, or not more than 5%, or not more than 3%, or not more than 1% R, R or S, R or R, S forms of the compound. The composition may contain a compound as a mixture of such stereoisomers, where the mixture may be a mixture of enantiomers (e.g., S, S and R, R) or diastereomers (e.g., S, S and R, S or S, R) in equal or unequal amounts. The composition may contain a compound as a mixture of 2 or 3 or 4 of these stereoisomers in any ratio of stereoisomers. Compounds disclosed herein having stereo centers in addition to those in the pyrido [4,3-b] indole ring structure include all stereochemical variants of such compounds, including, but not limited to, enantiomers and diastereomers in any respect, and include racemic and enantiomerically enriched and other possible mixtures. If stereochemistry is not explicitly indicated in the structure, the structure covers all possible stereoisomers of the depicted compound.

The synthesis and studies of the antipsychotic properties for cis (±) 2,8-dimethyl-2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indole and its dihydrochloride are described, for example, in the following Publications: Yakhontov, LN, Glushkov, RG, Synthetic therapeutic drugs. A.G. Natradze, the editor, Moscow Medicina, 1983, p. 234-237. The synthesis of compounds 2, 8 and 9, noted above as known from the literature, and data regarding their properties as serotonin antagonists are described, for example, in C.J. Cattanach, A. Cohen & B.H. Brown in J. Chem. Soc. (Ser. C) 1968, p. 1235-1243. The synthesis of compound 3, noted above as known from the literature, is described, for example, in N.P. Buu-Hoi, O. Roussel, P. Jacquignon, J. Chem. Soc, 1964, N 2, p. 708-711. N.F. Kucherova and N.K. Kochetkov (General chemistry (russ.), 1956, v. 26, p. 3149-3154), describe the synthesis of compound 4, noted above as known from the literature. The synthesis of compounds 5 and 6, noted above as being known from the literature, is described in A.N. Kost, M.A. Yurovskaya, T.V. Mel'nikova, Chemistry of heterocyclic compounds, 1973, N 2, p. 207-212. The synthesis of compound 7, noted above as known from the literature, is described by U, Horlein in Chem. Ber., 1954, Bd. 87, hft 4.463-p. 472. M. Yurovskaya and LL. Rodionov, in Chemistry of heterocyclic compounds (1981, No. 8, p. 1072-1078), describes the synthesis of methyl iodide of compound 8.

The first and second combination therapy compounds may be combined with a pharmaceutically acceptable carrier, and pharmaceutical compositions comprising the combination therapy are within the scope of the invention.

The invention also encompasses combination dosage forms for therapy, wherein the first and second combination therapy compounds are present in dosage form. As used herein, the term “dosage form” refers to a combination therapy composition that contains a specific dose of a first compound (such as dimebon) and a specific dose of a second compound (such as risperidone). The first and second compounds of the combined dosage form for therapy are present in amounts effective for the treatment of schizophrenia.

The invention further relates to kits comprising combination therapy as described herein. The kits may contain the first and second combination therapy compounds in the form of a dosage form (for example, the dosage form contains both dimebon and an atypical antipsychotic, such as risperidone) or as separate dosage forms (for example, dimebon is contained in a single dosage form, and the atypical antipsychotic, such like risperidone, contained in another dosage form). Kits also contain instructions for use. In one embodiment, dimebon and risperidone are used in the kit. Kits may be used for any one or more of the uses described herein and, accordingly, may contain instructions for any one or more of the claimed uses (e.g., treatment and / or prevention and / or delayed onset and / or development of schizophrenia).

Kits usually include suitable packaging. Kits may include one or more containers containing any compound or combination therapy described herein. Each component (if more than one component is available) can be packaged in separate containers, or some components can be combined in one container if cross-reactivity and shelf life allow it.

The kits may include a series of instructions, usually written instructions, although electronic storage media (e.g., a magnetic disk or optical disk) containing instructions are also acceptable regarding the use of component (s) in the methods of the present invention (e.g., treatment, prophylaxis and / or delays in the onset and / or development of schizophrenia The instructions included in the kit usually contain information on the components and their administration to the patient.

The following Examples are presented to illustrate, but not limit the invention.

All references cited herein are hereby incorporated by reference in their entirety.

EXAMPLES

Example 1. A method for evaluating the properties of compounds with respect to blocking NMDA-induced current

The drug is dimebon, 2,8-dimethyl-5- [2- (6-methylpyridyl-3) ethyl] -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole dihydrochloride Formulas :

was used as representative of the compounds described herein.

The experiments were performed by the method of fixing the potential on freshly isolated neurons of the rat cerebral cortex or on cultured rat hippocampal neurons. Cultivation neurons were obtained from the hippocampus of newborn rats (1-2 days) by trypsinization followed by pipetting. Cells suspended in culture medium were placed in an amount of 3 ml in the wells of a 6-well plate (Nunc) or in Petri dishes, in which poly-L-lysine coated glasses were first placed. The cell concentration was typically 2.5 × 10^-6 - 5 h 10^-6 cells / ml The culture medium consisted of a minimal medium Needle and medium DME / F12 (1: 1), supplemented with 10% calf serum, glutamine (2 mm), gentamicin (50 μg / ml), glucose (15 mm) and 20 mm KCl, with a pH adjusted to 7-7.4 using NaHCO₃. Tablets containing cultures were placed in CO₂-incubator at 37 ° C and 100% humidity. On the second or third day of cultivation, 10-20 μl of cytosine arabinoside was added. After 6-7 days of cultivation, 1 mg / ml glucose was added to the medium or the medium was replaced, depending on the next experiment. The cultured hippocampal neurons were placed in a 0.4 ml working chamber. The working solution had the following composition (mm): NaCl 150.0, KCl 5.0, CaCl₂ 2.6, MgSO_four H 7H₂O 2.0, HEPES 10.0, glucose 15.0, pH 7.36.

Transmembrane currents produced by deposition of NMDA were measured by the electrophysiological method of fixing potential in a full-cell configuration. The application of substances was carried out by the method of rapid superfusion. The currents were measured using borosilicate microelectrodes (resistance 3.0-4.5 mOhm) filled with the following composition (mm): KCl 100.0, EGTA 11.0, CaCl₂ 1.0, MgCl₂ 1.0, HEPES 10.0, ATP 5.0, pH 7.2. An EPC-9 instrument (HEKA, Germany) was used for registration. Currents were recorded on the Pentium IV PC hard drive using a pulse program also purchased from HEKA. The results were analyzed using the Pulsefit program (HEKA).

The application of NMDA caused incoming currents in cultured hippocampal neurons. Dimebon had a blocking effect on currents caused by the deposition of NMDA. The IC50 of dimebon ranged from 6.0 to 10 μM and averaged 7.7 ± 1.9 μM. MK-801 also caused blockade of NMDA-induced currents. This blockade had a clear “dependence of use”, in other words, the blocking effect caused by MK-801 depended on the previous agonist effect, that is, NMDA: the blocking effect increases in a series of successive agonist applications to a certain final value, which depends on the concentration of MK- 801. 1 μM MK-801 leads to blockade of NMDA-induced currents by 70 ± 15%. Preliminary perfusion of neurons with a solution containing dimebon at a concentration of 10 μM caused a decrease in the blocking effect of MK-801 to 40 ± 18%. For comparison, the effect of a competitive NMDA receptor antagonist, D-AP5, was studied (D-2-amino-5-phosphonovalerianic acid is a selective NMDA receptor antagonist). Directly at a dose of 5 μM, D-AP5 blocked NMDA-induced currents by 60-80%. Preliminary application of D-AP5 did not reduce the blocking effect of MK-801.

The results that were obtained are shown in Table 1.

Table 1.
Effect of substances on NMDA-induced currents in cultured rat hippocampal neurons. Substance Blockade of NMDA-induced currents (%) Dimebon 50-70% at 10 μM MK-801 70 ± 15% at 1 μM Dimebon + MK-801 40 ± 18% D-AP5 60-80% at 5 μM D-AP5 + MK-801 75 ± 17%

The results show that dimebon, although it is believed to be an NMDA receptor antagonist itself, is able to reduce the blocking effect of MK-801 on NMDA-induced currents in cultured rat hippocampal neurons. Although the mechanism of the blocking effect of dimebon on NMDA receptors has not yet been established, it does not have the neurotoxic effect that is characteristic of non-competitive blockers of the ion channels of the NMDA receptor - phencyclidine, MK-801, and ketamine. Based on these new results, it can be assumed that the reduction of the channel-blocking effect of MK-801 (and similarly phencyclidine) on NMDA receptors can lead to a decrease in their psychotomimetic effect and, therefore, to the elimination of symptoms characteristic of schizophrenia.

These results show that dimebon, along with its previously described properties, can be used to effectively treat schizophrenia.

Example 2. Using an in vivo model to determine the ability of the compounds of the invention to treat, prevent and / or delay the onset and / or development of schizophrenia

In vivo models of schizophrenia can be used to determine the ability of any of the hydrogenated pyrido [4,3-b] indoles described herein (eg, dimebon) to treat and / or prevent and / or delay the onset and / or development of schizophrenia.

In one model, phencyclidine is used to treat and / or delay the onset and / or development of schizophrenia to test the activity of one or more hydrogenated pyrido [4,3-b] indoles described herein, which is administered to an animal for a long time (e.g., not being a primate (rat) or a primate (monkey)), which leads to dysfunctions similar to those observed in people with schizophrenia. See Jentsch et al., 1997, Science 277: 953-955 and Piercey et al., 1988, Life Sei. 43 (4): 375-385). In this or other animal models, standard experimental protocols may be used.

Example 3. The use of clinical trials in humans to determine the ability of the compounds of the invention to treat, prevent and / or delay the onset and / or development of schizophrenia

If desired, any of the hydrogenated pyrido [4,3-b] indoles described herein (eg, dimebon) can also be tested in humans to determine the ability of a compound to treat, prevent and / or delay the onset and / or development of schizophrenia. Standard methods may be used for these clinical trials.

In one example method, patients with schizophrenia are enrolled in a Phase I study regarding tolerance, pharmacokinetics and pharmacodynamics of hydrogenated pyrido [4,3-b] indole using standard protocols. Phase II is then conducted, a double-blind, randomized, controlled trial to determine the effectiveness of hydrogenated pyrido [4,3-b] indole.

Example 4. The use of clinical trials in humans to determine the ability of the combination therapies of the invention to treat, prevent and / or delay the onset and / or development of schizophrenia

A clinical psychopharmacological study is currently underway to evaluate the clinical and neurocognitive characteristics and dynamics of biological markers over time, against the background of switching patients from first-generation drugs to the second generation of atypical antipsychotics and with the addition of dimebon. This study evaluates the effect of switching patients with chronic schizophrenia from traditional therapy to risotherapy monotherapy (serotonin-dopamine blocker) in accordance with clinical indicators, the results of neurocognitive tests, neurochemical, neuroimmunological, biochemical, genetic and morphological markers. Risolept is another term for risperidone, also sold under the brand name Risperdal in the United States, and refers to the compound 3- [2- [4- (6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl] ethyl ] -2-methyl-6,7,8,9-tetrahydropyrido [2,1-b] pyrimidin-4-one. The study also evaluates the possible increase in the clinical effect of antipsychotic therapy when dimebon, which has glutamate activity, is added to monotherapy with a serotonin-dopamine blocker.

The study includes 60 patients with a diagnosis of continuous paranoid and episodic-progressive schizophrenia with the current state of drug remission or with the development of drug remission, regardless of the syndrome that determines the current mental status. Thus, the study does not include patients who are completely resistant to psychotropic therapy. According to DSM-IV, these patients meet the criteria of 295.30, schizophrenia, paranoid type, chronic course.

At the first stage of the study, patients who agree on the basis of complete information to participate in the study and who meet the inclusion / exclusion criteria switch to monotherapy with an atypical antipsychotic (risplept), and the clinical stability of patients is assessed for more than two weeks. In the second stage, patients who are susceptible to the new treatment continue therapy in fixed doses (approximately 6 mg rispolepta, once a day), and those who are insensitive to the new treatment (non-responding) are excluded from the program and transferred to conventional therapy. In the third stage, after 4 weeks of monotherapy with an atypical antipsychotic, patients are divided into two groups based on a 1: 1 randomization and they are given an antiallergic drug with hypothetical glutamate neuroprotective activity (dimebon, approximately 20 mg three times a day) or placebo in addition to basic antipsychotic therapy. The third stage lasts 8 weeks. At the fourth stage (additional period), 6 months after completion of therapy within the framework of the described protocol, the stability of the characteristics achieved during the study is evaluated.

First stage Second stage Third stage Fourth stage 2 weeks 4 weeks 8 weeks Additional visit 6 months after completion of participation in the study One visit per week One visit per week One visit per week One visit per month

The study is carried out by selecting patients according to the following inclusion / exclusion criteria: 1. men, age from 18 to 65 years; 2. patients who have consented, based on full information, to participate in the study; 3. the patient meets the criteria of DSM-IV 295.30 schizophrenia, paranoid type, chronic course; 4. the mental state corresponds to the category of drug remission or the development of drug remission, regardless of the syndrome that determines the current mental status; 5. PANSS indicators for "disorganization of thinking", "suspiciousness", "hallucinatory behavior", "excitement" should not exceed "4"; 6. clinical symptoms of acute psychotic agitation should not be present - CGI - psychotic agitation should not exceed "moderate"; 7. the patient does not show symptoms of complete resistance to antipsychotic therapy (lack of positive dynamics in two courses of antipsychotic therapy with various antipsychotics); and 8. The psychotic state is not the result of an organic brain disease.

The study uses the methods detailed below.

1. Clinical / psychopathological (descriptive) method is used at each visit.

2. The psychometric method is used at the end of the first period, at the end of the second period, after 4 weeks of the third period and at the end of the third period.

• PANSS scale

• Calgary scale for evaluating depression during schizophrenia

Cgi-s

CGI-I

Research on Negative Symptoms-16 (NSA-16)

Aims

Bars

Sars

3. Neurocognitive functioning methods are used at the end of the second period, after 4 weeks of the third period and at the end of the third period. Some patients are evaluated using the following:

MEMORY SCALE WECHSLER_PODTEST V: DIRECT AND REVERSE PLAYBACK OF CIPHER LINES

MEMORY SCALE WECHSLER_PODTEST IV: LOGIC MEMORY (PART ONE, PART TWO.)

WECHSLER TEST, SUBTEST VII: ENCRYPTION

MEMORY SCALE WECHSLER_PTEST VII: PLAYING PAIRED ASSOCIATIONS

BENTON'S VISUAL TEST

TOWER OF LONDON

TEST STROOP

SHULTE TABLES

TASK FOR PERMANENT ATTENTION

WISKONSIN CARD SORT TEST

BOURDOHN MODIFIED TEST

4. Control of biological markers. The following markers can be evaluated:

• Neurochemical characteristics:

• Protein-like glutamine synthetase

• Cytochrome C oxidase

• Neuromorphology:

• Studies of the ultrastructure of lymphocytes and monocytes

• Neuroimmunology:

• Cytokines of the inflammation reaction (IL-1 beta, IL-2, IF gamma, tumor necrosis factor)

• Clinical Genetics

• Polymorphic changes in the genes of the neurotrophic factor of the brain

• Polymorphic variants of serotonin receptor type 2a genes

• Laboratory of molecular biochemistry

• Activity of leukocyte elastase

• activity of a-1 proteinase inhibitor

• C-reactive protein content

• The level of antibodies to neuroantigens - growth factors of nerves and the main protein of myelin

• Clinical Laboratory of Biochemistry

• Platelet Serotonin Level

• Platelet adhesion on the column and peak platelet delay time

• Determination of the half-life of Tetrahymena piriformis infusoria during incubation with blood serum from patients ("complete toxicity of the blood")

• The main parameters of lipid peroxidation in the blood of patients

Although the invention has been described above in detail by way of illustration and example for clarity of understanding, it will be apparent to one skilled in the art that some minor changes and modifications may be made. Therefore, the description and examples should not be construed as limiting the scope of the invention.

All references, publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims (7)

1. The method (a) of treating schizophrenia in a patient; (b) slowing the progression of schizophrenia in a patient who has been diagnosed with schizophrenia;
or (c) preventing or delaying the development of schizophrenia in a patient for whom there is a risk of developing schizophrenia, comprising administering to the patient an effective amount of a combination therapy including dimebon and risperidone. 2. The method according to claim 1, in which the introduction of dimebon enhances the therapeutic effect of risperidone compared with the introduction of risperidone in the absence of dimebon. 3. The method according to claim 1, in which risperidone is administered in an amount less than that required for risperidone as part of individual therapy to provide a comparable therapeutic effect. 4. The method according to claim 1, in which the patient's response to the administration of risperidone is enhanced. 5. A pharmaceutically acceptable composition for treating, preventing, slowing the progression or delaying the onset and / or development of schizophrenia, including dimebon and risperidone. 6. The composition according to claim 5, in which dimebon and risperidone are in a single dosage form. 7. A kit for treating, preventing, slowing the progression or delaying the onset and / or development of schizophrenia, including: (a) dimebon; (b) risperidone; and (c) instructions.